Mitochondrial Dynamics and Genetic Interactions in Multiple Sclerosis

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system characterized by inflammation, demyelination, and neurodegeneration. The development of MS involves a combination of genetic and environmental factors that contribute to its clinical heterogeneity.

Genetic Factors and Gene-Gene Interactions
Genome-wide association studies (GWAS) have identified over 200 genetic loci associated with MS risk. These include genes involved in immune regulation, such as the major histocompatibility complex (MHC) on chromosome 6p21, as well as genes encoding the interleukin-2 receptor (IL2RA) and interleukin-7 receptor (IL7RA). However, the identified genetic variants can only explain about 48% of the observed heritability in MS. This suggests that gene-gene interactions, where the effect of one gene depends on the genotype of another gene, play an important role in MS susceptibility and clinical presentation.

For example, a study found an interaction between variants in the CLECL1 and EFCAB13 genes, which are both associated with MS risk. Individuals carrying the risk alleles in both genes had a significantly higher risk of developing MS compared to those with risk alleles in only one gene.

Mitochondrial Genes and Mitonuclear Interactions
Emerging evidence suggests that mitochondrial DNA (mtDNA) variants and their interactions with nuclear-encoded mitochondrial genes (mitonuclear interactions) may also contribute to MS susceptibility and clinical heterogeneity.

A study found that the mitochondrial haplogroup U, a group of related mtDNA variants, was associated with an increased risk of MS. Additionally, a trend towards an association was observed between a variant in the NDUFS2 gene, which is involved in the mitochondrial complex I pathway, and MS risk. These findings indicate that mitochondrial dysfunction and mitonuclear interactions may play a role in the pathogenesis of MS, potentially through mechanisms related to oxidative stress and energy metabolism in the central nervous system.

In conclusion, the clinical heterogeneity of multiple sclerosis is influenced by a complex interplay between genetic and environmental factors, as well as interactions between nuclear and mitochondrial genes. Understanding these gene-gene and gene-environment interactions is crucial for improving our understanding of MS pathogenesis and developing personalized treatment approaches.

Reference:
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Wigner, P., Dziedzic, A., Synowiec, E., Miller, E., Bijak, M., & Saluk-Bijak, J. (2022). Variation of genes encoding nitric oxide synthases and antioxidant enzymes as potential risks of multiple sclerosis development: a preliminary study. Scientific Reports, 12(1), 10603.
Slim, L., Chatelain, C., Foucauld, H. D., & Azencott, C. A. (2022). A systematic analysis of gene–gene interaction in multiple sclerosis. BMC Medical Genomics, 15(1), 100.
Kozin, M., Kulakova, O., Kiselev, I., Baulina, N., Boyko, A., & Favorova, O. (2020). Mitonuclear interactions influence multiple sclerosis risk. Gene, 758, 144962.